1. Field of the Invention
The present invention relates to a method of immune/gene combination therapy that has an effect of suppressing growth of an intractable solid tumor and is useful for treatment of such a tumor, and a therapeutic composition used for said method.
2. Description of Related Art
Allogeneic hematopoietic stem cell transplantation (alloHSCT) often leads to a significant graft-versus-tumor (GVT) effect, and has proven to be an effective therapeutic approach for several types of leukemia, particularly acute and chronic myelogenous leukemia. Recently, alloHSCT has been applied not only for hematological malignancies but also for solid cancers such as renal and breast cancers. However, the benefit of the GVT effect is often offset by the occurrence of graft-versus-host disease (GVHD), a potentially fatal adverse effect primarily mediated by donor T cells. It is commonly believed that in MHC-matched alloHSCTs the target antigens for a GVT effect include tumor-associated antigens (TAAs) and ubiquitously or tissue-specifically expressed minor histocompatibility antigens (mHAs), whereas the targets for GVHD are mHAs. Therefore, efforts to selectively enhance a donor T cell response to TAAs may provide a means to augment antitumor activity without a concomitant increase in toxicity.
The interferon alpha (IFN-α) protein is a cytokine with pleiotropic biological properties that include antiviral activity, regulation of cell proliferation, induction of apoptosis and immunomodulation. The cytokine has been used worldwide for treatment of a variety of cancers including certain hematological malignancies such as chronic myeloid leukemia and solid tumors such as melanoma and renal carcinoma. However, clinical experiences with IFN protein therapy for many other solid cancers have generally not been encouraging. In the conventional regimen of IFN clinical trials, the recombinant IFN-α protein is systemically administered through subcutaneous or intramuscular routes. However, since the protein is rapidly degraded in the blood circulation and only 0.01% of subcutaneously injected IFN-α can reach the target organs, the delivery of the IFN-α protein might be insufficient and/or result in an unsustainable level in the tumor site, which may be the cause of the diminished antitumor effect in previous clinical trials based on the IFN-α protein. In contrast, since gene transfer allows an increased and sustained local concentration of IFN-α in the target sites with minimal leakage of the cytokine into the systemic blood circulation, the use of IFN-α is expected to improve the therapeutic effect and safety in the context of gene therapy.
In fact, we previously demonstrated that intratumoral injection of IFN-α expressing adenovirus vector induced the direct cytotoxicity in the pancreatic cancer (US 2005/0260167 A1). In addition, the gene transfer of IFN-α augmented antitumor immunity by a stimulation of natural killer (NK) cells and cytotoxic T lymphocytes and the maturation of antigen-presenting cells. Therefore, we expect that an IFN-A gene transfer could enhance the GVT effect by promoting recognition of TAAs by the donor immune system in alloHSCT recipients, and also that alloHSCT, on the other hand, could augment the therapeutic efficacy of an IFN-α gene transfer by providing a “fresh” immune system in which tolerance to tumor cells is not yet induced. In this study, using an MHC (H-2d)-matched mouse alloHSCT model, we found that an intratumoral IFN-α gene transfer significantly enhanced the antitumor effects of alloHSCT against a murine colon and renal cancer. Importantly, GVHD was not exacerbated in any of the treated mice, suggesting the augmentation of tumor-specific immunity of donor T cells by the IFN-α gene transfer.